It has been well known that, as a result of vigorous research and development of anticancer agents for many years, various kinds of anticancer agents are now being used in chemotherapy to various types of cancer and therapeutic effect is achieved thereby. However, it has been also known that there is no anticancer agent which is effective on all types of cancer and there is a limitation for the therapeutic effect of anticancer agent on cancer.
As one of the causes for the limitation in the therapeutic effect on cancer by anticancer agent, it has been reported that hypoxic condition inside the solid cancer participates in resistance to its therapy. For example, in Non-Patent Document 1 (Matthews N E, Adams M A, Maxwell L R, Gofton T E, Graham C H. Nitric oxide-mediated regulation of chemosensitivity in cancer cells. J. Natl. Cancer Inst., 2001; 93: 187-1885), it is shown that, in experiments where several kinds of cancer cell lines are actually used, hypoxic condition promotes the resistance of cancer cells to anticancer agent. In this document, it is made clear that, when an anticancer agent is mixed with culture medium of cancer cell lines, the surviving rate is as high as two-fold or more even if the cancer cells are directly exposed to the anticancer agent as compared with the case where they are exposed in normoxic condition provided that they are exposed in hypoxic condition. It is also made clear that hypoxic condition suppresses an endogenous production of nitric oxide (NO) whereby it enhances the resistance of the cancer cells to anticancer agent and that administration of an exogenous NO donor improves the resistance to anticancer agent by hypoxic condition. Besides that, in Non-Patent Document 2 (Jordan B F, Misson P D, Demeure R, Baudelet C, Beghein N, Gallez B. Changes In tumor oxygenation/perfusion induced by the NO donor, Isosorbide dinitrate, In comparison with carbogen: monitoring by EPR and MRI. Int. J. Radiation Oncology Biol. Phys., 2000; 48: 565-570), it is suggested that isosorbide dinitrate which is a NO donor improves oxygen pressure inside the cancer due to an increase in blood flow. In Non-Patent Document 3 (Liang B C. Effects of hypoxia on drug resistance phenotype and genotype in human glioma cell lines. J. Neurooncol., 1996; 29: 149-155), it is made clear that, when glioma cell line is placed in hypoxic condition, it shows resistance to anticancer agent. In Non-Patent Document 4 (Sanna N, Rofstad E K. Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro. Int. J. Cancer, 1994; 58: 258-262), it is made clear that, when human melanoma cell line is placed in hypoxic condition, it shows resistance to anticancer agent. Thus, according to those reports, even when anticancer agent is merely distributed in large quantities in cancer cells, death of cancer cells is not accelerated unless hypoxic condition in tumor tissues is improved. Non-Patent Document 1 and Non-Patent Document 2 suggest that a NO donor is able to effectively function in improvement of hypoxic condition inside the solid cancer.
However, in any of the reports, it is not proved that NO actually enhances the therapeutic effect of anticancer agent on cancer in human clinical medicine. Rather, there are many reports which suggest that NO has an action of increasing the tumor size and promoting its progress. For example, in Non-Patent Document 5 (Gallo O, Masini E, Morbidelli L, Franchi A, et al. Role of nitric oxide in angiogenesis in head and neck cancer. J. Natl. Cancer Inst., 1998; 90: 587-596), a NO synthase (NOS) participating in NO production in tissue preparation of human head and neck cancer is investigated and it is shown that, in advanced cancer cases accompanied by metastasis to lymph node, expressed amount of NOS is high and blood vessel density in lymph node is high in a group where metastasis to lymph node is positive. In this document, an investigation using cornea of rabbit is also conducted for tumor angiogenetic effect of NO on cancer tissues prepared from human head and neck cancer cases. According to that, it is suggested that, in a group to which L-NAME which is a NOS inhibitor is administered, tumor angiogenesis is significantly little and progress of cancer is suppressed as compared with a control group and it is shown that NO has a promoting action for increase and progress of cancer tissues via tumor angiogenesis. In Non-Patent Document 6 (Edwards P, Cendab J C, Topping D B, Moldawer L L, Mackay S, Copeland E M, Lind D S. Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. J. Surg. Res., 1996; 63: 49-52), it is shown that, when an experiment using cultured cells where NO production is promoted by stimulation of LPS/IFN-γ using EMT-6 cells (breast cancer cell line of mice) is conducted, growth of tumor cells is suppressed while, when the same cells are transplanted to BALB/c mouse and stimulated by LPS/IFN-γ, tumor tissues and lung metastasis increased to an extent of two-fold as compared with a control group and that experimental results are entirely opposite between an experiment using cultured cells (in vitro experiment) and an animal experiment (in vivo experiment). In the Non-Patent Document 7 (Ambs S, Merriam W G, Ogunfusika M O, Bennett W P, Ishibe N, et al. p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nature Med., 1998; 4: 1371-1376), an influence of NO on angiogenesis and cancer progress is investigated in an animal experiment where a human cancer cell line into which NOS gene is introduced so as to conduct a NO synthesis in a constant manner is transplanted to nude mice having no thymus. Here, relation to the presence/absence of an activity of cancer suppressive gene p53 is investigated and it is shown that, in tumor tissues where cancer cell line having a p53 activity (wild type p53) is transplanted to nude mice, an endogenous NO suppresses the growth of tumor cells while, in tumor tissues where cancer cell line having poor p53 activity (mutant p53) is transplanted to nude mice, the endogenous NO promotes VEGF expression and angiogenesis, and promotes the growth of tumor cells. In Non-Patent Document 8 (D C Jenkins, I G Charles, L L Thomsen, D W Moss, L S Holmes, S A Baylis, P Rhodes, K Westmore, P C Emson, S Moncada. Roles of Nitric Oxide in Tumor Growth. Proc. Natl. Acad. Sci. USA, 1995; 92: 4392-4396), it is shown that, inhuman breast cancer and cancer in a gynecologic field, NO production and cancer growth show a positive correlation. In Non-Patent Document 9 (Lala P K, Chakraborty C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol., 2001; 2: 149-156), it is shown that NOS of a derived type participates in mutation of p53 of tumor of colon, lung and throat and that NO stimulates the growth of tumor via activation of cyclooxygenase-2 (COX-2). Thus, according to those reports, it is strongly suggested that, in establishing a therapy of cancer by anticancer agent in human clinical medicine, the use of NO has a possibility of causing adverse effects to patients such as increase or progress of cancer.
As mentioned above, with regard to an action of NO to cancer, each of the reports mentioning it participates in the direction of suppressing the cancer and the reports mentioning it participates in the direction of worsening the cancer are present in large numbers being supported by scientific proof and a scientific evaluation therefor is in a chaotic state. Moreover, as shown in Non-Patent Document 6, it is never rare that the experimental results are entirely contrary between an experiment using cultured cells and an animal experiment. In view of such circumstances, in Non-Patent Document 1 for example, it is shown that resistance of cancer cell line to anticancer agent induced by hypoxic condition is improved by a NO donor in an experiment using cultured cells and, although such a finding will be surely valuable for showing one direction for future research, it is not possible to conclude from such a finding that a NO donor has an action of shrinking the cancer tissues or an action of enhancing the effect of anticancer agent. So, it is all the more that, in human clinical medicine, a conclusion that a NO donor enhances the effect of anticancer agent is unable to be done and should not be done.
In Patent Document 1 (JP 2004-508279 A), there is proposed a method of administering a NO donor as a potassium channel activator as a method for a selective transfer of anticancer agent to cancer where permeability of blood vessel or sending blood to cancer cells to anticancer agent is enhanced. However, issue of a jumped conclusion that a NO donor enhances the effect of anticancer agent only by appealing an increase in transition of an anticancer agent to tumor tissues by an increase in permeability through blood vessel without actual confirmation of enhancement of NO donor in the action of anticancer agent to cancer tissues even in animal experiment is not convincing at all under the present status where scientific evaluation for the action of NO to cancer is in chaos as mentioned above. Patent Document 1 is far behind the conclusion that a NO donor results in enhancement of effect of anticancer agent in actual human clinical medicine. In fact, with regard to data showing that improvement in therapeutic effect for cancer was able to be achieved by that method, no data is available even for animal experiment in Patent Document 1.
Therefore, an object of the present invention is to provide an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer.